PHARMACOLOGICAL ACTION OF TETRA-ALKYL-AMMONIUM COMPOUNDS. 385 



tetra-ethyl-ammonium chloride. If the minimal stimulus necessary to excite the 

 sciatic nerves of a frog with brain and cord pithed be determined, and a dose of tetra- 

 ethyl-ammonium chloride insufficient to paralyse be injected, it will be found that 

 the nerves react to a smaller stimulus after the intoxication than before. In an 

 experiment in which the right thigh was ligatured, the left sciatic nerve prior to the 

 injection was irritable with the secondary coil at 23 cm., the right with the coil at 

 21 '5 cm. Seven minutes after the injection of 0*1 mg. per gramme of frog into the 

 abdominal cavity, irregular and fibrillary contractions appeared in the trunk muscles, 

 and some minutes later extended to the thigh and left leg muscles. Later, owing to 

 the difficulty of preventing diffusion of this substance by simply ligaturing the leg, 

 contractions appeared in the right leg muscles. Twelve minutes after the injection 

 the left sciatic was irritable with the secondary coil at 24 '5 cm., the right sciatic with 

 the coil at 20 cm. Two hours after the administration the left sciatic reacted with 

 the coil at 29 cm., the right sciatic with the coil at 25 cm. In a similar manner an 

 increase in the irritability of the nerves in mammals may be shown (see fig. 3) ; and 

 it may also be demonstrated on the isolated nerve-muscle preparation of the frog. 

 The marked increase in the tremors which often follows a voluntary movement or 

 mechanical or electrical stimulation also points to this condition. Not infrequently 

 tremors which have failed to develop owing to an insufficient dose, or which for the 

 time being have been in abeyance, may be induced by gently probing a muscle or by 

 electrically stimulating its nerve ; and in the course of experiments on the effects of 

 applying small drops of a solution to muscles, I have even seen them initiated in one 

 muscle by the contractions of another muscle playing in part over it. Nevertheless, 

 while increased irritability undoubtedly exists during an intoxication with tetra- 

 ethyl-ammonium chloride, these contractions, although less actively, have continued 

 in many of my experiments to a time when the animal was obviously paralysed and 

 when electrical stimulation of the sciatic nerves showed them to be unirritable or 

 much less sensitive than normally. It seems difficult, therefore, to avoid the 

 conclusion that the block in the early stages of the paralysis occurs in a proximal 

 portion of the myo-neural junction, or that the whole of the myo-neural junction is 

 not simultaneously, perhaps not uniformly, paralysed. 



The muscular contractions are readily produced by applying minute drops of a 

 solution above 1 in 1000 to an exposed muscle, after the method of Langley. I have 

 usually employed for the purpose a fine hypodermic needle with the point cut off, 

 but have also employed a fine sable brush. In some cases the surface of the muscle 

 was dried with filter-paper prior to the application, in order to prevent running of the 

 drop. The procedure appeared to render the muscle less sensitive, and delayed, often 

 markedly, the appearance of the tremors, but it did not materially influence the sub- 

 sequent effects. When an isotonic solution was applied to the sartorius, for example, 

 tremors of a portion of the muscle proximal to the drop, quickly followed by a brief 

 tonic contraction of a longitudinal strip of muscle about the width of the drop, occurred 



